The present application claims priority under 35 U.S.C. xc2xa7371 from PCT Application No. PCT/GB00/02799 (published under PCT Article 21(2) in English), filed on Jul. 24, 2000 which claims the benefit of Great Britain Application Serial No. 9917092.0, filed on Jul. 22, 1999, the disclosures of which are incorporated by reference herein in their entireties.
This invention relates to the treatment of diseases or disorders which are dependent on angiogenesis.
Angiogenesis, the development of new blood vessels from an existing vascular bed, is a complex multistep process that involves the degradation of components of the extracellular matrix and then the migration, proliferation and differentiation of endothelial cells to form tubules and eventually new vessels. Angiogenesis is important in normal physiological processes including, by example and not by way of limitation, embryo implantation; embryogenesis and development; and wound healing. Angiogenesis is however uncommon in healthy adults.
Angiogenesis is also involved in pathological conditions such as: ocular neovascular glaucoma; diabetic retinopathy; corneal graft rejection; vitamin A deficiency; Sjorgen""s disease; acne rosacea; mycobacterium infections; bacterial and fungal ulcers; Herpes simplex infections; systemic lupus; rheumatoid arthritis; osteoarthritis; psoriasis; chronic inflammatory diseases (eg ulcerative colitis, Crohn""s disease); hereditary diseases such as Osler-Weber Rendu disease and haemorrhagic teleangiectasia.
The vascular endothelium is normally quiescent. However upon activation endothelial cells proliferate and migrate to form microtubules which will ultimately form a capillary bed to supply blood to developing tissues and, of course, a growing tumour. A number of growth factors have been identified which promote/activate endothelial cells to undergo angiogenesis. These include, by example and not by way of limitation; vascular endothelial growth factor (VEGF); transforming growth factor (TGFb); acidic and basic fibroblast growth factor (aFGF and bFGF): and platelet derived growth factor (PDGF).
It is now well recognised that angiogenesis is a feature of a variety of diseases or disorders and that such conditions can be treated by administration of angiogenesis inhibitors. Many such inhibitors have been discovered. A number of endogenous inhibitors of angiogenesis have been discovered, examples of which are angiostatin and endostatin, which are formed by the proteolytic cleavage of plasminogen and collagen XVIII respectively. Both of these factors have been shown to suppress the activity of pro-angiogenic growth factors such as vascular VEGF and bFGF. Both of these factors suppress endothelial cell responses to VEGF and bFGF in vitro, and reduce the vascularisation and growth of experimental tumours in animal models.
Our PCT application WO 98/24421 relates to the treatment of patients suffering from highly vascular tumours which comprises administering dextrin sulphate to the patient. The mechanism of action of dextrin sulphate on highly vascular tumours was not known.
We have now found that dextrin sulphate is an angiogenesis inhibitor. New vessel formation is inhibited by a direct action effect of dextrin sulphate on endothelial cells. Its effect is to prevent endothelial cells coming together to form new vessels and then forming new blood vessels. Both processes are a prerequisite for the progression of an angiogenesis-dependent condition, such as the continued growth of a vascular tumour and of its metastatic lesions. The administration of dextrin sulphate to a patient can therefore provide a way of preventing angiogenesis and thereby arresting the progression of an angiogenesis-dependent condition.
Accordingly, the present invention provides a method of treating an angiogenesis-dependent condition, other than a highly vascular tumour, which comprises administering dextrin sulphate to the patient.
Considerable efforts has been directed towards the development of drugs which interfere with angiogenesis. One such group is sulphated polysaccharides. Their anti-angiogenic activity was first demonstrated using a combination of heparin and cortisone. This was followed by reports of several other sulphated polysaccharides which demonstrated anti-angiogenic activity in vitro. The most notable of these compounds was a naturally occurring sulphated polysaccharide-peptidoglycan (SP-PG) which is produced by the bacterium Arthrobacier sp (strain AT-25). SP-PG inhibited the growth of AIDS-associated Kaposi""s sarcoma-derived spindle cells at concentrations that were not cytotoxic. It also blocked the angiogenesis which is induced by AIDS-Kaposi""s sarcoma cells in nude mice. However, no clinical benefit was observed when SP-PG was administered intravenously to patients with AIDS-related Kaposi""s sarcoma.
In a Phase I clinical trial of dextrin 2-sulphate in patients with late stage AIDS, we demonstrated that the direct administration of dextrin 2-sulphate into the lymphatic circulation using the intra-peritoneal route resulted in a significant and sustained fall in the viral load of HIV-1. No clinical or biochemical toxicity was seen even after the administration of several grams of the drug. During the course of the clinical trial, we noted the clinical regression of Kaposi""s sarcoma in three patients and these observations were the subject of WO 98/24421. Here, we provide in vitro and in vivo data for a mechanism of action of the anti-angiogenic activity of sulphated dextrins which is independent of their anti-HIV-1 activity.